A neuroactive steroid with a therapeutically interesting constellation of actions at GABA_A and NMDA receptors.

ABSTRACT: Neuroactive steroids are an ascendant class of treatment for neuropsychiatric illness. Effects on ligand-gated neurotransmitter receptors appear to be a major mechanism of action. Here we describe a neuroactive steroid with a unique constellation of receptor actions. MQ-221 is a sulfated, 3β-hydroxy neurosteroid analogue that inhibits NMDAR function but also potentiates GABA_AR function, thereby exhibiting unusual but potentially clinically desirable effects. Although the compound also exhibited features of other sulfated steroids, namely activation-dependent inhibition of GABA_AR function, net potentiation dominated under physiological conditions. Potentiation of GABA_AR function was distinct from the mechanism governing potentiation by anesthetic neurosteroids. Inhibition of NMDAR function showed weaker channel activation dependence than pregnanolone sulfate (3α5βPS). MQ-221 was unique among four stereoisomers explored in the pattern of effects at GABA_A and NMDARs. Taken together, MQ-221 may represent a new class of compound with unique psychoactive effects and beneficial prospects for treating neuropsychiatric disorders.

SUBMITTER: Ziolkowski L 

PROVIDER: S-EPMC7736525 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature